ME02414B - TREATMENT OF MORBUS CROHN WITH LAQUINIMOD - Google Patents

Abstract

The present invention provides a pharmaceutical composition for use in treating a patient suffering from Kronoveboli, which contains lacquinimod or a pharmaceutically acceptable salt thereof, which is effective in treating a patient suffering from Crohn's disease.

Description

 

 

Treatment of Crohn's disease with laquinimod

 

Description of the invention

 

Background of the invention

 

Crohn's disease (CD) and ulcerative colitis (UC) are the two main types of inflammatory bowel disease (IBD) - the generic classification of a group of non-specific, idiopathic inflammatory disorders of the gastrointestinal (GI) tract, which also includes indeterminate colitis (IC). Indeterminate colitis refers to up to 15% of IBD cases in which it is not possible to differentiate between CD and UC (Kasper, 2008). Both CD and UC are usually chronic in nature, and the course of the disease is characterized by exacerbations and remissions.

CD can occur in any part of the GI tract, but it most commonly affects the distal ileum and colon. It is characterized by transmural inflammation of the gastrointestinal wall, interrupted by normal tissue, which leads to the characteristic endoscopic and radiographic appearance of the disease. In approximately half of cases, biopsy specimens reveal the pathognomonic histology of non-caseating granulomas (Friedman, 2001). Although CD usually presents as acute or chronic intestinal inflammation, the inflammatory process progresses to one or two different forms of the disease: the fibro-stenotic-obstructive or penetrating-fistulous form, each of which has a different treatment and prognosis (Friedman, 2001).

The characteristic inflammatory picture of Crohn's disease includes abdominal pain, diarrhea, fever and weight loss, which can also include complications in the form of intestinal fistulas, obstruction, or both. Fistulas can occur directly next to the intestine, skin, bladder or in other places. Obstruction, if present, initially appears and recedes due to edema and spasm of the intestinal wall; further progression can lead to chronic scarring and formation of strictures. Perianal disease is common and may present as an anal fissure, perianal fissure, or abscess (Friedman, 2001; Wu, 2007).

Signs of disease outside the intestinal system may also occur, and include joint inflammation (e.g. peripheral arthritis, ankylosing spondylitis), skin lesions (e.g. erythema nodosum, pyoderma gangrenosum), eye changes (e.g. iritis, uveitis) and disorders liver (eg, hepatic steatosis, primary sclerotic cholanitis (Friedman, 2001; Wu, 2007).

The incidence of CD is different in different geographical areas. Northern countries such as the USA, Great Britain, Norway and Sweden have the highest rates of disease. The incidence of CD in the US is approximately 7 per 100,000. The countries of southern Europe, southern Africa and Australia have a lower incidence, from 0.9 to 3.1 per 100,000. The disease is rare in Asia and South America (Friedman, 2001).

The maximum occurrence of Crohn's disease is between 15 and 30 years of age, while the second maximum occurrence occurs between 60 and 80 years of age (Friedman, 2001).

The underlying cause of CD is unknown. There are four main factors that influence the pathophysiology of CD: genetics, immune deregulation, epithelial barrier dysfunction and the composition of the microbial flora. Evidence suggests that genetic predisposition leads to a deregulated intestinal immune response to an environmental, food, or infectious agent (Friedman, 2001; Wen, 2004). Several studies indicate that CD is a disease mediated by T-helper 1 (TH-1) cells, and that excessive activity of TH1 cells leads to the production of a wide range of pro-inflammatory cytokines (including interleukin (IL)-1, IL-2, and tumor necrosis factor (TNF)-�), and that the imbalance between pro-inflammatory and anti-inflammatory reactivity is a critical component of CD (Hendrickson, 2002). However, no antigen was found that could be the trigger.

In the absence of a key diagnostic test, the diagnosis of Crohn's disease is based on endoscopic, radiographic, and pathologic findings documenting focal, asymmetric transmural, or granulomatous features. Laboratory abnormalities include nonspecific markers of inflammation, such as increased sedimentation and C-reactive protein (CRP) concentrations. In more severe cases, findings may include hypoalbuminemia, anemia, and leukocytosis (Friedman, 2001; Wu, 2007).

There is no definitive treatment or cure for CD. The main therapeutic goals are the reduction of signs and symptoms, the induction and maintenance of remission and, most importantly, the prevention of disease progression and complications.

Sulfasalazine and other 5-aminosalicylic acid-based agents, antibiotics such as metronidazole and ciprofloxacin, corticosteroids, immunosuppressants such as azathioprine and 6-mercaptopurine, and biological agents such as anti-TNF� agents and anti-integrins have been shown to prevent leukocyte infiltration, useful in inducing remission and/or in its maintenance (Targan, 1977; Hanauer, 2002; Colombel, 2007; Ghosh, 2003; Sandborn, 2005; Schreiber, 2005; Schreiber, 2007; Kozuch, 2008). Many of these medicinal products, however, are only moderately effective and are associated with side effects that represent a significant challenge (Hommes, 2003; Thomas, 2004; Colombel, 2004; Van Assche, 2005; Vermeire, 2003; Sweetman, 2006). . In addition, newer biological agents are administered parenterally, which is relatively inconvenient. Therefore, there is a definite need for alternative therapies with a better risk-benefit profile and a more comfortable route of administration than currently available options.

A procedure for the treatment of Crohn's disease using laquinimod is described. Laquinimod is a novel synthetic compound with high oral bioavailability that has been proposed as an oral formulation for relapsing-remitting multiple sclerosis (MS). Laquinimod and its sodium salt are described, for example, in US Pat. 6,077,851. The effects of laquinimod on Crohn's disease have not been published.

WO2007146331 describes a preparation containing a mixture of polypeptides in the form of a tannate salt, where each polypeptide is a copolymer of the amino acids L-glutamic acid, L-alanine, L-tyrosine and L-lysine, methods and preparation of such a polypeptide.

US200804382 describes the use of alpha 4 inhibitors in the treatment of inflammatory and autoimmune diseases, such as multiple sclerosis, Crohn's disease, rheumatoid arthritis and asthma.

 

Brief description of the invention

 

The subject application also provides a pharmaceutical preparation for use in treating a patient suffering from Crohn's disease, comprising laquinimod or a pharmaceutically acceptable salt thereof, which is effective in treating a patient suffering from Crohn's disease.

 

Detailed description of the invention

 

The subject application provides a pharmaceutical preparation containing laquinimod for use in the treatment of a patient suffering from Crohn's disease.

It is desirable that the treatment involves the periodic administration, in said patient, of that amount of laquinimod or its pharmaceutically acceptable salt which is effective in the treatment of the patient.

In one embodiment, said amount of laquinimod is effective in alleviating symptoms of Crohn's disease in a patient, inducing a clinical response, inducing or maintaining clinical remission, inhibiting disease progression, or inhibiting a disease complication in said patient.

In another embodiment, said amount of laquinimod is effective in reducing the patient's Crohn's disease activity index, reducing the patient's C-reactive protein concentration, reducing the patient's fecal calprotectin concentration, or reducing the number of open draining fistulas in the patient.

In one embodiment, said amount of laquinimod is effective in reducing steroid dependence of said patient.

In one embodiment, the Crohn's disease activity index of the patient is reduced by at least 100 points. In another embodiment, the Crohn's disease activity index of the patient is reduced to below 150.

In one embodiment, the number of open draining fistulas in the patient is reduced by at least 50% compared to the period prior to the initiation of periodic administration.

In one solution, said periodic administration is oral.

In one embodiment, said amount is administered in a unit dose of 0.5 mg laquinimod. In yet another solution, said periodic application is daily application. In another embodiment, said amount of laquinimod is 0.5-2.0 mg/day. In yet another embodiment, said amount of laquinimod is 1.0 mg/day. In yet another embodiment, said amount of laquinimod is 1.5 mg/day. In yet another embodiment, said amount of laquinimod is 2.0 mg/day.

In one solution, a loading dose with an amount different from the maintenance dose is administered over a period of time at the beginning of periodic administration. In another solution, a loading dose with an amount twice the maintenance dose is administered over a period of time at the beginning of periodic administration. In another solution, a loading dose with an amount that is different from the maintenance dose is administered over two days at the beginning of periodic administration. In another solution, a loading dose with an amount twice the maintenance dose is administered over two days at the beginning of periodic administration.

In one solution, the patient had active moderate-to-severe Crohn's disease prior to laquinimod administration. In yet another solution, the patient had a Crohn's disease activity index score of 220-450 prior to laquinimod administration. In another embodiment, the patient had a C-reactive protein concentration exceeding 5 mg/l prior to laquinimod administration. In another solution, the patient's diagnosis before administration ruled out the possibility of indeterminate colitis. In another further solution, the patient's diagnosis before administration ruled out the possibility of ulcerative colitis.

In one embodiment, periodic administration is continued for 8 weeks or longer.

In one embodiment, said laquinimod is in the form of laquinimod sodium.

In one embodiment, said patient is a human.

In one solution, the procedure further involves the administration of 5-aminosalicylic acid, antibiotics, corticosteroids, immunosuppressants or biological agents including TNF� agents and anti-integrins.

The subject application also provides the use of laquinimod for the manufacture of a medicament for the treatment of a patient suffering from Crohn's disease.

All combinations of different elements described here are covered by the scope of protection of the subject invention.

A pharmaceutically acceptable salt of laquinimod, when that term is used in the subject application, includes lithium, sodium, potassium, magnesium, calcium, manganese, copper, zinc, aluminum and iron. Salt formulations of laquinimod and the process for their preparation are described, for example, in US Patent Application No. 2005/0192315 and in PCT International Application Publication no. WO 2005/074899, each of which is incorporated herein by reference.

A dosage unit may contain a single compound or mixtures of its compounds. A dosage unit can be obtained for oral dosage forms, such as tablets, capsules, pills, powders and granules.

Laquinimod may be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier), selected according to the intended route of administration and in accordance with conventional pharmaceutical practice. The unit will be in a form suitable for oral administration. Laquinimod can be administered alone, but is usually mixed with a pharmaceutically acceptable carrier and administered simultaneously in the form of a tablet or capsule, liposome or agglomerated powder. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsules or tablets can be easily formulated and can be made to be easy to swallow or chew; other solid forms include granules and bulk powder. Tablets may contain suitable binders, lubricants, diluents, disintegrants, colors, flavorings, flow improvers, and solubilizing agents.

Specific examples of techniques, pharmaceutically acceptable carriers and excipients that can be used to formulate oral dosage forms according to the foregoing invention are described, e.g. in US Patent Application No. 2005/0192315 and in PCT publications of international applications no. WO 2005/074899, WO 2007/047863 and WO/2007/146248, each of which is incorporated herein by reference.

General techniques and preparations for making dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, eds. 1979); Pharmaceutical Dosage Forms: Tablets (Lieberman et al., 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd ed. (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences Volume 7 (David Ganderton, Trevor Jones, editors, 1992); Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Editor, 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, Volume 61 (Alain Rolland, Editor, 1993); Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, editors); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, Volume 40 (Gilbert S. Banker, Christopher T. Rhodes, editors.) These references are incorporated into the subject application in their entirety by reference.

The tablets may contain suitable binders, lubricants, disintegrants, colors, flavors, flow improvers and solubilizers. For example, for oral administration in the form of a tablet or capsule dosage unit, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier, such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, dicalcium phosphate , calcium sulfate, mannitol, sorbitol, microcrystalline cellulose and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn starch, natural and synthetic gums such as acacia, tragacanth or sodium alginate, povidone, carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in the above dosage forms include sodium oleate, sodium stearate, sodium benzoate, sodium acetate, sodium chloride, stearic acid, sodium stearyl fumarate, talc and the like. Disintegrants include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum, croscarmellose sodium, sodium starch glycolate, and the like.

 

 

 

 

 

 

 

Definitions of terms

 

When used in the subject application and unless otherwise indicated, each of the following terms shall be defined as follows.

The "amount" or "dose" of laquinimod, measured in milligrams, refers to the milligrams of laquinimod acid present in the preparation, regardless of the form of the preparation.

As used in the subject application, "loading dose" refers to an initial higher dose of drug that may be administered at the beginning of a treatment regimen before tapering down to a lower, "target dose" or "maintenance dose."

As used in the subject application, the "Crohn's Disease Activity Index" or "CDAI" is a research instrument developed by W. R. Best and colleagues at the Midwest Regional Health Center in Illinois in 1976 (Best, 1976) to quantify the symptoms of patients suffering from Crohn's disease . The mentioned index is the most widely used instrument for evaluating the activity of Crohn's disease (Best, 1976; Best, 1979; Sandborn, 2002) and consists of eight factors/variables.

The mentioned eight variables are added after adjustment based on weights. CDAI components and weights are shown in the following table:

 

A clinical or laboratory variable

Ponder

Number of loose or soft stools (sum of all days within seven days)

x 2

Abdominal pain (rated on a scale of intensity from 0 to 3) (sum of all days during seven days)

x 5

General condition, evaluated subjectively, on a scale from 0 (good) to 4 (terrible) (sum of all days during seven days)

x 7

The presence of complications of Crohn's disease

x 20

Use of diphenoxylate or loperamide for diarrhea in the past week (0 = no, 1 = yes)

x 30

Presence of a mass in the abdomen (0 no, 2 as possible, 5 as definite)

x 10

Absolute hematocrit deviation of 47% in men and 42% in women

x 6

Percentage deviation from standard mass

x 1

 

The first 4 of these variables and the presence of fever above 37.8oC are reported by the patient himself in his diaries, while the other 4 are evaluated during the study visit. Height and standard body mass estimates are based on standard height and mass tables.

The total score on the CDAI ranges from 0 to approximately 600, with the higher the score, the more active the disease. A CDAI score of less than 150 points indicates "clinical remission" of Crohn's disease, from 150 to 219 points indicates "active mild Crohn's disease", between 220 and 450 points indicates "active moderate Crohn's disease" and more than 450 points indicates "active severe Crohn's disease" ".

"Clinical response" means that the patient's symptoms of Crohn's disease have been alleviated, in terms of intensity and/or number. "Clinical remission" means that the symptoms of Crohn's disease in the specified patient have decreased, in terms of intensity and/or number, to below a defined level, e.g. below 150 points on the CDAI scale. "Clinical remission" and "clinical response" can be measured according to the EMEA draft guideline on the development of new medicinal products for the treatment of Crohn's disease. The EMEA guidelines define "clinical remission" as a reduction of the CDAI score to a total score below 150 points and "clinical response" if a remission is achieved or a reduction of at least 100 points in the total score on the CDAI scale is observed, compared to the initial state at the end of the treatment period (EMEA, 2007).

"Indeterminate colitis" or "IC" is used clinically in patients suffering from some form of inflammatory bowel disease, in whom a definitive diagnosis of either ulcerative colitis (UC) or Crohn's disease (CD) has not been established, either by colonoscopy or colonic biopsy prior to colectomy. Although some patients diagnosed with indeterminate colitis later develop UC or CD, studies show that during a follow-up period of 10 years (median), many patients retain the diagnosis of indeterminate colitis (Guindi, 2004).

"Inhibition" of disease progression or disease complications in a patient means prevention or reduction of disease progression and/or disease complications in said patient.

As used in the subject application, "C-reactive protein" or "CRP" is an inflammatory mediator whose concentration is elevated under conditions of acute re-inflammation and rapidly decreases to normal levels as the inflammation resolves. Crohn's disease can be characterized based on how the disease behaves: mostly without strictures and without penetration (inflammatory), with strictures or with penetration (Silverberg, 2005). The origin of symptoms such as diarrhea, fatigue or abdominal pain (affecting the CDAI score) can be multifactorial and does not necessarily show a correlation with the presence of pronounced inflammatory lesions of the gastrointestinal (GI) tract. Crohn's disease, which predominantly shows the absence of strictures and penetration (inflammatory), can be characterized by high concentrations of CRP. Therefore, CRP can serve as a surrogate marker for monitoring inflammatory disease activity and response to treatment (Solem, 2005; Denis, 2007; Chamouard, 2006).

As used in the subject application, "calprotectin" is an antimicrobial protein that binds calcium and zinc and is released by granulocytes. This protein can be detected in the stool, and its concentration reflects the number of polymorphonuclear leukocytes (PMN) that migrate into the intestinal lumen. Therefore, it is considered a biological marker for intestinal inflammation.

As used in the subject application, an "effective" amount, when referring to an amount of laquinimod, is that amount of laquinimod that is sufficient to produce the desired therapeutic response without avoidable side effects (such as toxicity, irritation, or allergic response). , which corresponds to a reasonable risk-benefit ratio, when used in accordance with the subject invention.

When used in the subject application, the term "treatment" includes e.g. induction of inhibition, withdrawal or stagnation of the disorder.

As used in the subject application, "pharmaceutically acceptable carrier" refers to a carrier or excipient that is suitable for use in humans and/or animals without undue side effects (such as toxicity, irritation, or allergic response), and that implies a reasonable benefit-risk ratio. It can be a pharmaceutically acceptable solvent, suspending agent or carrier, for delivering the compound of the present invention to the patient.

It is understood that, if a range is specified, all values within that range, including tens of those values, are covered by the scope of protection of the subject invention. For example, "5-10%" includes 5.0%, 5.1%, 5.2%, 5.3%, 5.4%, etc. up to 10.0%.

The subject invention will be better explained by consideration of the experimental details which follow, but those skilled in the art will readily appreciate that the specific experiments described in detail are merely illustrative of the subject invention which is more fully described in the claims which follow the examples.

 

 

 

 

 

 

 

Experimental data

 

Example 1: Clinical Study (Phase IIa) - Evaluation of Oral Laquinimod in Active Moderate to Severe Crohn's Disease

A multicenter, randomized, double-blind, placebo-controlled, phase IIa study with sequential dose-ranging cohorts was conducted to evaluate escalating doses of laquinimod in active moderate-to-severe Crohn's disease.

 

Title of the study

A multicenter, randomized, double-blind, placebo-controlled, sequential cohort dose-finding phase IIa study to assess the safety, tolerability, and clinical effect of escalating doses of laquinimod in active moderate-to-severe Crohn's disease.

 

Participating countries and number of study centers

Europe (Belgium, France, Italy, Holland, Spain, Poland and Great Britain), Israel and South Africa, in about 50 centers.

 

Number of patients

4 sequential cohorts were determined with approximately 45 patients for each cohort, randomized 2:1 (<���patients on laquinimod and <15 on placebo). A total of <180 patients with Crohn's disease were enrolled.

 

Investigational medicinal product (IMP) & dosage

One or more capsules containing 0.5 mg of laquinimod or the corresponding placebo are administered orally once daily:

1st cohort - laquinimod 0.5 mg (1 x 0.5) or corresponding placebo;

2nd cohort - laquinimod 1.0 mg (2 x 0.5) or corresponding placebo;

3rd cohort - laquinimod 1.5 mg (3 x 0.5) or corresponding placebo; and

4th cohort - laquinimod 2.0 mg (4 x 0.5) or matching placebo.

 

Capsules containing 0.5 mg of laquinimod were obtained using 0.534 mg of laquinimod sodium per capsule (corresponding to 0.5 mg of laquinimod acid). The capsules were prepared using a mixture proportional to the 0.6 mg capsules described in PCT International Application No. PCT/US2007/013721 (WO 2007/146248). The capsules were obtained according to the procedure described in PCT International Application no. PCT/US2007/013721 (WO 2007/146248), each of which is incorporated by reference into the subject application.

The shock dose regimen, which includes a double maintenance dose, was administered during the first two days of the trial drug treatment. After that, starting on day 3, the daily maintenance dose (intended dose) is administered.

Table 1 provides a brief overview of the number of capsules and the total dose administered daily in each of the 4 cohorts in the study, at different time points during the treatment period. "BID" means that the dose is administered twice a day. "QD" means that the dose is administered once a day.

 

Cohort

And 1

And 2

Day 3 and beyond

0.5 mg/plc capsule/and

dose/dose

0.5 mg/plc capsule/dan

dose/dose

0.5 mg/plc capsule/and

dose/dose

1

1+1 (BID)

1 mg/placebo

1+1 (BID)

1 mg/placebo

1 (QD)

0,5 mg/placebo

2

2+2 (BID)

2 mg/placebo

2+2 (BID)

2 mg/placebo

2 (QD)

1 mg/placebo

3

3+3 (BID)

3 mg/placebo

3+3 (BID)

3 mg/placebo

3 (QD)

1,5 mg/placebo

4

4+4 (BID)

4 mg/placebo

4+4 (BID)

4 mg/placebo

4 (QD)

2 mg/placebo

 

Patients were required to keep a CDAI diary for each day of the screening period and, if randomized, on each day of treatment and in the control period. Scores obtained from the seven consecutive diary entries prior to the baseline visit, as well as for each of Weeks 1, 2, 4, 6, 8, and 12 contribute to the total CDAI score at each time point.

Allowed prior standard treatment is maintained throughout the study (including during the control period, as defined herein).

 

Duration of the study

Each cohort (dose group) is evaluated for up to 14 weeks

Screening: between 1-2 weeks

Treatment period: 8 weeks

Control period (monitoring): 4 weeks

Population of participants in the study

Patients suffering from moderate to severe Crohn's disease (CS), as determined by a Crohn's Disease Activity Index (CDAI) score of 220-450 (including cutoffs).

 

Study design

This multicenter, randomized, double-blind, placebo-controlled, sequential cohort dose-finding phase IIa study to assess the safety, tolerability, and clinical efficacy of escalating doses of laquinimod in active moderate-to-severe Crohn's disease is the first study to evaluate the safety, tolerability, and efficacy of laquinimod in patients with active CD.

This study examined laquinimod doses of 0.5, 1.0, 1.5, and 2.0 mg daily. Each dose was tested sequentially in a specific cohort.

Patients' suitability for participation in this study was assessed 1 to 2 weeks before the initial visit.

Approximately 45 eligible patients were assigned to each cohort. Patients were randomly assigned, in a 2:1 ratio, to one of the following two treatments:

1. Oral laquinimod (< patients).

2. Appropriate oral placebo (<15 patients).

 

Each subsequent cohort was subjected to screening and randomization only when the following two conditions were met:

1.                     Randomization of at least 45 patients for the previous cohort and closure of the screening and randomization process for the previous cohort.

2. The safety commission decided to proceed to the next dose level.

 

This decision is based on a review of data collected from at least 15 patients who completed 4 weeks of treatment in the previous cohort, as well as all other data obtained in the study for any of the previous cohorts.

All investigators working on the study were informed when screening and/or randomization was closed for the previous cohort and opened for the next cohort/dose level. All patients in the screening phase are allowed to be randomized (if they can participate in the study) to the previous cohort or the next cohort, whichever is open at the time of randomization/initial visit.

The safety committee can determine for any of these safety assessments that dose limiting toxicity (DLT) has been reached. The criteria for DLT are not predetermined and are based solely on the best medical judgment of the safety committee.

In the event that a dose-limiting toxicity is reached, the safety committee has the following options in terms of decisions it can make:

1. Closure of the current cohort without continuation to the next dose level/cohort; and

2. Immediate termination of the study.

 

Scheduled clinic visits are conducted at screening, baseline, and weeks 1, 2, 4, 6, and 8. Laquinimod/placebo treatment is discontinued at week 8, followed by a follow-up and end-of-study visit at week 12. Discontinuing patients of the study drug before the visit in week 8, they go to the final control visit within 4 weeks (28 days) of stopping taking the study drug.

Unscheduled visits, for security reasons or for any other reason, may be conducted at any time during the study.

During the duration of the study, the CDAI score is determined along with routine safety laboratory tests and PK analysis.

Based on previous pharmacokinetic studies, laquinimod reaches steady state (steady state) after approximately 10-12 days of maintenance dosing. In order to reduce the time to steady state and potentially reduce the time to response, the loading dose regimen described in the following text is used to allow steady state to be reached within approximately 6-7 days.

The shock dose regime of the tested drug is given during the first two days of treatment (day 1/initial visit and thereafter). The first loading dose of the study drug during the study is administered at the study center. The loading dose is twice the maintenance dose in the first two days, and is administered twice a day (BID) with an interval of 12 hours between administrations. From that day forward, starting on day 3, the dosing regimen consists of the intended once-daily (QD) dose (see Table 1):

1.                     Day 1 (initial visit): loading dose of the drug (maintenance dose at zero hour, in the study center and maintenance dose after 12 hours). The total dose is twice the maintenance dose.

2.                     Day 2: loading dose of the test drug (maintenance dose at zero hour and maintenance dose after 12 hours). The total dose is twice the maintenance dose.

3.                      Day 3: Maintenance dose/planned dose of the study drug.

 

All previous standard treatment is kept stable during the study (including during the control period, as defined here).

 

PK analysis

Pharmacokinetic (PK) substudy - an additional study performed in a subgroup of study centers

Blood samples for PK analysis - 24-hour profile - were taken from patients in the first cohort (0.5 mg/placebo) at week 4.

One blood sample, before administration of the drug dose, is taken in the first cohort (0.5 mg/placebo) during the first week as part of the assessment of the stationary state.

 

Population PK study (PPK)

Blood samples for PPK determination are collected at weeks 2 and 8 from all patients in all cohorts. One sample is taken before the administration of the dose and one sample after the administration of the dose, in a time period of 0.5 to 6 hours.

 

A pharmacogenetic substudy

Blood samples for the pharmacogenetic substudy are obtained from all patients who sign a separate informed consent form and after approval by the Ethics Committee (EC).

 

Allowed comparative drugs during the study

In general, the dose of drugs that are allowed for comparative use is kept stable during the entire study (including during the control period). Any new drugs/treatments for CD or dose increase, not permitted by the protocol, throughout the entire treatment period during the study, lead to a major violation of the protocol and are considered a treatment failure. Dose reductions or dosing regimens not permitted by the protocol also lead to major protocol violations.

Surgical interventions for CD, biological treatment or new immunosuppressive drugs, during the entire study period, are considered treatment failure and lead to early treatment discontinuation.

 

5-ASA compounds

The use of 5-ASA compounds was maintained at a stable level throughout the study period.

 

Antibiotics

The use of antibiotics for the treatment of Crohn's disease was maintained at a stable level throughout the study. Treatment of acute infections (not related to Crohn's disease) is allowed.

 

Corticosteroids

The dose of oral corticosteroids remains stable throughout the study:

1.                      Oral systemic corticosteroids - increase or decrease not exceeding 2.5 mg prenisolone per day (or equivalent dose) compared to baseline.

2. Budenoside - no change from the initial state is allowed.

3. IV or IM corticosteroids or corticosteroid enemas are not allowed.

 

Immunosuppressants

Immunosuppressive treatment permitted by the protocol (AZA/6MP/MTX) was maintained at a stable level during the entire study period. The introduction of new immunosuppressive drugs is not allowed.

 

The rest

1.                     Anti-diarrhoeal drugs, analgesics, NSAIDs and topical preparations are allowed (including topical dermatological, ophthalmic or inhaled steroids).

2.                     Probiotic use is maintained at a stable rate throughout the study.

 

Inclusion/exclusion criteria

 

Inclusion criteria

Patients must meet all inclusion criteria to be included in the study:

1. Men and women aged 18-75 (including thresholds).

2.       Patients diagnosed with Crohn's disease at least 3 months before screening, which is documented appropriately and where the diagnosis is supported endoscopically or radiologically (within 36 months before screening and after surgical resection), or by surgical intervention.

3.       Patients with moderate to severe Crohn's disease, determined by a CDAI score of 220-450 (including cut-offs).

4.       Patients with a C-reactive protein (CRP) concentration greater than 5 mg/l at the time of screening or at any time between screening and the initial visit, including at the initial visit, OR documented endoscopic evidence of mucosal ulceration within 4 weeks prior to the initial visit .

(a)       Evidence of mucosal ulceration is defined as the presence of at least 2 ulcers ≥10 mm.

(b)       The documentation shall include the endoscopy report with photographs or video recording confirming the allegations.

5.       Patients who are willing and able to provide written, informed consent.

 

Exclusion criteria

Any of the following criteria leads to the exclusion of the patient from entering the study:

1.       Patients with a diagnosis of indeterminate colitis.

2.       Patients with positive stool culture results for the presence of enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter or Clostridia Difficile toxin test), during screening.

3.       Patients who have had bowel surgery within 3 months prior to screening or who are planning elective surgery or hospitalization during the duration of the study (which could affect adherence to study conditions or its outcome).

4. Patients with clinically significant short bowel syndrome.

5.       Patients with clinically significant obstructive syndromes of the GI tract.

6. Patients with intra-abdominal abscess.

7.       Patients with fistula or clinical or radiological evidence of abscess.

8.       Patients with ileostomy, colostomy, or on parenteral nutrition.

9.       Patients with a clinically significant or unstable medical or surgical condition that, in the opinion of the investigator, would prevent safe and complete participation in the study, as determined by medical history, clinical examination, EKG, laboratory testing, or imaging. Such conditions may include:

a. Cardiovascular or pulmonary disorder not well controlled by standard treatment permitted by study protocol.

b. Renal, metabolic or hematological diseases.

c. Any form of acute or chronic liver disease.

d.                     Known positive status for human immunodeficiency virus (HIV).

e. Systemic infection at screening.

f. Family history of long QT syndrome.

Mr. History of drug and/or alcohol abuse.

h. A serious psychiatric disorder is present.

10.       Patients with an increase ≥ 2x the upper limit of normal (ULN) serum concentration of the following parameters, at screening: ALT, AST, GGT, ALKP or direct bilirubin.

11.       QTc interval that is >500 msec (as determined by machine testing), obtained by:

a. Dva EKG scan u toku screening visite ILI

b. Mean values calculated from 2 ECG recordings at the initial visit.

12.       Patients with a history of any malignancy in the past year, before screening, excluding basal cell carcinoma.

13. Patients treated with oral corticosteroids (eg prednisolone/budenoside), who started treatment less than 4 weeks before screening.

14.       Patients treated with more than 20 mg/day of prednisolone (or equivalent) or > 6 mg/day of budenizide, for the treatment of CD, at screening or whose corticosteroid dose regimen is not stable for at least 2 weeks before the initial visit. [stable dose is defined as an increase or decrease of ≤ 2.5 mg prednisolone (or equivalent), no change in budenoside, and no IV and IM steroid administration during the last two weeks before the baseline visit].

15.       Patients treated with 5-ASA compounds who are not on a stable dose for at least 2 weeks before screening.

16.       Patients treated with antibiotics, for CD, who are not on a stable dose for at least 2 weeks before screening.

17.       Patients treated with 6-MP, AZA, or MTX, who started treatment within 12 weeks before screening or who are not on a stable dose for at least 6 weeks before screening.

18.       Patients treated with anti-TNF drugs within 4 weeks prior to screening [the percentage of patients previously treated with anti-TNF drugs was limited to approximately 60% of patients randomized to each cohort. The sponsor notified all principal investigators when the quota for patients previously treated with anti-TNF drugs was met for each of the cohorts].

19.       Patients treated with cyclosporine, tacrolimus, mycophenolate mofetil or thalidomide within 2 months before screening.

20.       Patients treated with natalizumab within 6 months before screening.

21.       Patients who used any other investigational drug during the 3 months prior to screening.

22.       Use of a CYP3A4 inhibitor during the 2 weeks before the initial visit (1 month for fluoxetine).

23. Amiodarone use within 2 years before screening.

24.       Women who are pregnant or lactating at the time of screening, or intend to be or do so during the study period.

25.       Women in the reproductive part of the life cycle who do not use acceptable methods of contraception. Acceptable methods of contraception in this study are: surgical sterilization, intrauterine implants, oral contraceptives, contraceptive patches, long-acting injectable contraceptives, partner vasectomy, double protection procedure (condom or diaphragm with spermicide).

26.       Known hypersensitivity to the drug that would prevent the application of the study drug, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.

27.       Patients who are unable to adhere to the planned schedule of study visits and procedures.

 

Criteria for withdrawal from the study/treatment failure

1.                     According to the instructions of the investigator, a patient who does not respond to the treatment protocol is withdrawn from the study.

2. Emergency therapy for Crohn's disease (any new drugs/treatments or dose increases, not permitted by the protocol), throughout the treatment period during the study, lead to a major violation of the protocol and are considered treatment failures.

3.                     Surgical interventions for CD, biological treatment or new immunosuppressive drugs, during the entire study period, are considered treatment failures and lead to early treatment discontinuation.

 

 

 

 

Follow-up plan and safety rules for stopping the study

In the event of any of the events listed below, the patient's participation in the study is terminated without delay. The patient is monitored until resolution or stabilization of symptoms or laboratory results that previously showed an abnormality:

1.                      Any increase in ALT or AST to ≥3 times ULN, combined with either an increase in INR ≥ 1.5 times ULN or an increase in total bilirubin ≥ 2 times ULN.

2.                     Any elevation of ALT or AST to ≥3 times ULN, with onset or worsening of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia.

3.                      Any elevation of ALT or AST to ≥5 but <8 times ULN, lasting for ≥2 weeks or on repeated measurements.

4.                      Any elevation of ALT or AST to ≥8 times ULN.

 

Outcome measures

 

Clinical effects

Exploratory efficacy outcome measures for this study were chosen in accordance with the draft EMEA guidelines for the treatment of active Crohn's disease/inducing remission (EMEA, 2007).

1.                     Proportion of patients in clinical remission (total CDAI score <150) at weeks 4, 6, 8 and 12.

2.                     Proportion of patients showing response to treatment (reduction of at least 100 CDAI points from baseline, or remission), at weeks 4, 6, 8 and 12.

3. Elapsed time until remission.

4. Elapsed time until response.

5. C-reactive protein (CRP) changes from baseline at weeks 2, 4, 6, 8 and 12.

6.                     Change in faecal calprotectin results from baseline, at weeks 2, 4, 6, 8 and 12.

7.                     Proportion of patients with a reduction of at least 50% in the number of open, draining fistulas, compared to baseline.

 

 

 

Safety/tolerability

1. Adverse events (AE).

2. Clinical laboratory values.

3. Vital signs.

4. EKG.

5. Proportion of patients who stop treatment prematurely.

6. Proportion of patients who stop treatment prematurely due to AE.

7. Time elapsed until premature termination of treatment.

8. Time elapsed until premature discontinuation of treatment due to AE.

 

Determination of the maximum tolerated dose

During any safety assessment, the safety committee may determine that a dose-limiting toxicity (DLT) has been reached. The criteria for DLT are not predetermined and are based solely on the best medical judgment of the safety committee.

The highest tolerable dose is defined as the dose below the dose at which no further dose increase is allowed, according to the decision of the safety commission.

 

Pharmacokinetics/Population PK

Steady-state parameters (AUCtau, Cmax, and Cmin) were calculated only for the 0.5 mg dose (in a subset of study centers).

A population approach is used to fit plasma concentration-time data for all dosage groups, if possible. The model evaluates the effect of different covariates on the pharmacokinetics of laquinimod (all centers, all cohorts).

 

the results

0.5 mg/dan

An oral dose of laquinimod at 0.5 mg/day in patients with moderate to severe Crohn's disease (CDAI score of 220-450) reduces the symptoms of Crohn's disease in patients, leads to a clinical response, induces and/or maintains clinical remission, and(li) inhibits disease progression and (or) disease complications in the patient. More specifically, the use of laquinimod reduces the score that a given patient achieves on the Crohn's Disease Activity Index, reduces the concentrations of C-reactive protein and(or) fecal calprotectin in the said patient and(or) reduces the number of open draining fistulas in the said patient. Moreover, an oral dose of 0.5 mg of laquinimod per day in patients with moderate to severe Crohn's disease reduces the dependence of said patient on steroids.

 

1.0 mg/dan

An oral dose of laquinimod at 1.0 mg/day in patients with moderate to severe Crohn's disease (CDAI score of 220-450) reduces symptoms of Crohn's disease in patients, results in a clinical response, induces and/or maintains clinical remission, and(li) inhibits disease progression and (or) disease complications in the patient. More specifically, the use of laquinimod reduces the score that a given patient achieves on the Crohn's Disease Activity Index, reduces the concentrations of C-reactive protein and(or) fecal calprotectin in the said patient and(or) reduces the number of open draining fistulas in the said patient. Moreover, an oral dose of 1.0 mg laquinimod daily in patients with moderate to severe Crohn's disease reduces the steroid dependence of said patient.

 

1.5 mg/dan

An oral dose of laquinimod at 1.5 mg/day in patients with moderate to severe Crohn's disease (CDAI score of 220-450) reduces the symptoms of Crohn's disease in patients, leads to a clinical response, induces and/or maintains clinical remission, and(li) inhibits disease progression and (or) disease complications in the patient. More specifically, the use of laquinimod reduces the score that a given patient achieves on the Crohn's Disease Activity Index, reduces the concentrations of C-reactive protein and(or) fecal calprotectin in the said patient and(or) reduces the number of open draining fistulas in the said patient. Moreover, an oral dose of 1.5 mg laquinimod daily in patients with moderate to severe Crohn's disease reduces the steroid dependence of said patient.

 

2.0 mg/dan

An oral dose of laquinimod 2.0 mg/day in patients with moderate to severe Crohn's disease (CDAI score of 220-450) reduces symptoms of Crohn's disease in patients, results in a clinical response, induces and/or maintains clinical remission, and inhibits disease progression and (or) disease complications in the patient. More specifically, the use of laquinimod reduces the score that a given patient achieves on the Crohn's Disease Activity Index, reduces the concentrations of C-reactive protein and(or) fecal calprotectin in the said patient and(or) reduces the number of open draining fistulas in the said patient. Moreover, an oral dose of 2.0 mg laquinimod daily in patients with moderate to severe Crohn's disease reduces the steroid dependence of said patient.

 

Reference

 

1.       PCT International Application Publication No. 2007/047863, published on 26/04/2007, international date of application submission 18/10/2006.

2.       PCT International Application Publication No. WO 2007/146248, published 21.12.2007, international filing date 12.6.2007.

3.       Best WR, Becktel JM, Singleton JW, et al. Development of a Crohn’s Disease Activity Index. Gastroenterology 1976; 70:439-444.

4.       Best WR, Becktel JM, Singleton JW. Rederived values of the eight coefficients of the Crohn’s Disease Activity Index (CDAI). Gastroenterology 1979; 77:843-6.

5.       Chamouard P, Richert Z, Meyer N, Rahmi G. Diagnostic value of C-reactive protein for predicting activity. Clin Gastroenterol hepatol 2006; 4:882-887.

6.       Colombel JF, Loftus EV Jr., Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn’s disease: the Mayo clinic experience in 500 patients. Gastroenterol 2004; 126:19-31.

7.       Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, Schreiber S, Byczkowski D, Li J, Kent JD, Pollack PF. Adlimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterol 2007; 132(1):52-65.

8.       Comi G, Pulizzi A, Rovaris M, Abramsky 0, Arbizu T, Boiko A, Gold R, Havrdova E, Komoly S, Selmaj K W, Sharrack B, Filippi M, za LAQ/5062 Study Group. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, radomised, double-blind, placebo-controlled phase IIB study. Lancet 2008; 371:2085-92.

9.       Denis MA, Reenaers C, Fontaine F, Blaïche J, Louis E. Assessment of Endoscopic Activity Index and Biological Inflammatory Markers in Clinically Active Crohn’s disease with Normal C-reactive Protein Serum Level. Inflamm Bowel Dis 2007; 13:1100-1105.

10.       EMEA 2007. Points to consider on clinical investigation of medicinal products for the management of Crohn’s disease. CPMP/EWP/2284/99 Rev.1.

11.       Friedman S, Blumberg RS. Inflammatory Bowel Disease. U: Braunwald E., Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, urednici, Harrison’s Principles of Internal Medicine. New York: McGraw-Hill Professional, 2001:1679-92.

12.       Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn’s disease. N. Engl J Med 2003; 348:24-32.

13.       Guindi M & Riddell, RH (2004) "Indeterminate Colitis" J. Clin. Pathol. 57:1233-1244.

14.       Hanauer SB, Feagan BG, Lichtenstein GR et al. Maintenance infliximab for Crohn’s disease: the accent I randomised trial. Lancet 2002; 359.

15.       Hendrickson BA, Gokhale R, Cho JH. Clinical aspects and pathophysiology of inflammatory bowel disease. Clin Microbiol Rev 2002; 15:79-94.

16.       Hommes DW, Van Deventer SJH. Inflixmab therapy in Crohn’s disease: safety issues. Neth J Med 2003; 61:100-104.

17.       Jonsson S, Andersson G, Fex T, Fristedt T, Hedlund G, Jansson K, Abramo L, Fritzson I, Pekarski O, Runstrom A, Sandin H, Thuvesson I, Bjork A. Synthesis and biological evaluation of new 1,2-dihydro-4-hydroxy-2-oxo-3- quinolinecarboxamides for treatment of autoimmune disorders: structure-activity relationship. J Med Chem. 8.4.2004. 47(8):2075-88.

[ PubMed ] 18. Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. (2008). Harrison’s principles of internal medicine (17th grade). New York: McGraw-Hill Medical Publishing Division. ISBN 978-0-07-146633-9.

19.       Kozuch PL, Hanauer SB. Treatment of inflammatory bowel disease: A review of medical therapy. World J Gastroenterol; 2008; 14(3):354-377.

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21.       Lund Research Center AB, Active Biotech Group, Sweden. The inhibitory activity of PNU-215062 on acute experimental autoimmune encephalomyelitis in the mouse and a comparison with the activity of roquinimex (PNU- 212616). 9830161, Final Report, februar 1999.

22.       Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione, Sanders M, Schreiber S, Targan S, van Deventer S, Goldblum R, Despain D, Hogge GS, Rutgeerts P; Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005; 353(18):1912-25.

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24. Schreiber S, Khaliq-Kareemi M, Lawrence IC, Thomasen OO, Hanauer SB, McColm J, Bloomfield R, Sandborn WJ; Maintenance therapy with centrolizumab pegol for Crohn’s disease. N Engl J Med. 2007; 357:239-50.

25.       Schreiber S, Rutgeerts P, Fedorak RN, et al. A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn’s disease. Gastroenterol 2005; 129:807-818.

26.       Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Berstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus Jr EV, Pena AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol; 2005; 19 dodatak A:5-36.

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30.       Targan SR, Hanauer SB, van Deventer SJ et al. A short-term study of chimeric monoclonoal antibody cA2 to tumor necroseis factor alpha for Crohn’s disease. N. Engl J Med 1977; 337:1029-35.

31.       Thomas CW Jr., Weinshenker BG, Sandborn WJ. Demyelination during anti-tumor necrosis factor alpha therapy with infliximab for Crohn’s disease. Inflamm Bowel Dis 2004; 10:28-31.

32.       Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med 2005; 353:362-8.

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35.       Wu, George. Crohn Disease, Emedicine, 2007.

 

 

 

Teva Pharmaceutical Industries Ltd.

5 Basel Street P.O. Box 3190

49131 Petach-Tikva, ISRAEL

 

 

Representative:

 

 

Patent claims 1. A pharmaceutical preparation for use in the treatment of a patient suffering from Crohn's disease, characterized by the fact that it contains a pharmaceutically acceptable carrier and a certain amount of laquinimod or its pharmaceutically acceptable salt, and which is effective in the treatment of a patient suffering from Crohn's disease. 2. Pharmaceutical preparation according to patent claim 1, characterized in that it essentially consists of one or more pharmaceutically acceptable carriers and a certain amount of laquinimod or its pharmaceutically acceptable salt. 3. Pharmaceutical preparation according to patent claims 1 or 2, characterized in that the specified amount of laquinimod is effective in alleviating the symptoms of Crohn's disease in the patient, inducing a clinical response, inducing or maintaining clinical remission, inhibiting the progress of the disease or inhibiting the complication of the disease in the said patient. 4. Pharmaceutical preparation according to patent claims 1 or 2, characterized in that the specified amount of laquinimod is effective in reducing the activity index of Crohn's disease in a patient, reducing the concentration of C-reactive protein in a patient, reducing the concentration of fecal calprotectin in a patient or reducing the number of open draining fistulas in a patient of the said patient. 5. Pharmaceutical preparation according to any one of patent claims 1 to 4, characterized in that it is prepared for oral administration. 6. Pharmaceutical preparation according to any one of patent claims 1 to 5, characterized in that it contains a unit dose of 0.5 mg of laquinimod or its pharmaceutically acceptable salt. 7. Pharmaceutical preparation according to any one of patent claims 1 to 6, characterized in that it is prepared for administration once a day. 8. Pharmaceutical preparation according to any one of patent claims 1 to 7, characterized in that it is formulated for the use of laquinimod or its pharmaceutically acceptable salt in a dose of 0.5-2.0 mg per day. 9. Pharmaceutical preparation according to any one of claims 1 to 8, characterized in that the patient suffered from moderate to severe Crohn's disease. 10. A pharmaceutical preparation according to any one of claims 1 to 9, characterized in that the patient had a score on the Crohn's Disease Activity Index of 220-450. 11. Pharmaceutical preparation according to any one of patent claims 1 to 10, characterized in that the patient had a concentration of C-reactive protein over 5 mg/l. 12. Pharmaceutical preparation according to any one of patent claims 1 to 11, characterized in that it is prepared for use for a period of 8 weeks or longer. 13. A pharmaceutical preparation according to any one of claims 1 to 12, characterized in that laquinimod or its pharmaceutically acceptable salt is in the form of laquinimod sodium. 14. A pharmaceutical preparation characterized by essentially consisting of a certain amount of laquinimod or its pharmaceutically acceptable salt, effective in the treatment of a patient suffering from Crohn's disease and a certain amount of 5-aminosalicylic acid, antibiotics, corticosteroids, immunosuppressants, TNF� agents or anti-integrins . 15. Use of a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a patient suffering from Crohn's disease. Teva Pharmaceutical Industries Ltd. 5 Basel Street P.O. Box 3190 49131 Petach-Tikva, ISRAEL   Agent:       Treatment of Crohn's disease with laquinimod   Abstract       The subject invention provides a pharmaceutical preparation for use in the treatment of a patient suffering from Crohn's disease, which contains laquinimod or a pharmaceutically acceptable salt thereof, and which is effective in the treatment of a patient suffering from Crohn's disease. Teva Pharmaceutical Industries Ltd. 5 Basel Street P.O. Box 3190 49131 Petach-Tikva, ISRAEL     Representative:

 

1. A pharmaceutical preparation for use in the treatment of a patient suffering from Crohn's disease, characterized in that it contains a pharmaceutically acceptable carrier and a certain amount of laquinimod or its pharmaceutically acceptable salt, and which is effective in the treatment of a patient suffering from Crohn's disease.

 

2. Pharmaceutical preparation according to patent claim 1, characterized in that it essentially consists of one or more pharmaceutically acceptable carriers and a certain amount of laquinimod or its pharmaceutically acceptable salt.

 

3. Pharmaceutical preparation according to patent claims 1 or 2, characterized in that the specified amount of laquinimod is effective in alleviating the symptoms of Crohn's disease in the patient, inducing a clinical response, inducing or maintaining clinical remission, inhibiting the progress of the disease or inhibiting the complication of the disease in the said patient.

 

4. Pharmaceutical preparation according to patent claims 1 or 2, characterized in that the specified amount of laquinimod is effective in reducing the activity index of Crohn's disease in a patient, reducing the concentration of C-reactive protein in a patient, reducing the concentration of fecal calprotectin in a patient or reducing the number of open draining fistulas in a patient of the said patient.

 

5. Pharmaceutical preparation according to any one of patent claims 1 to 4, characterized in that it is prepared for oral administration.

 

6. Pharmaceutical preparation according to any one of patent claims 1 to 5, characterized in that it contains a unit dose of 0.5 mg of laquinimod or its pharmaceutically acceptable salt.

 

7. Pharmaceutical preparation according to any one of patent claims 1 to 6, characterized in that it is prepared for administration once a day.

 

8. Pharmaceutical preparation according to any one of patent claims 1 to 7, characterized in that it is formulated for the use of laquinimod or its pharmaceutically acceptable salt in a dose of 0.5-2.0 mg per day.

 

9. Pharmaceutical preparation according to any one of claims 1 to 8, characterized in that the patient suffered from moderate to severe Crohn's disease.

 

10. A pharmaceutical preparation according to any one of claims 1 to 9, characterized in that the patient had a score on the Crohn's Disease Activity Index of 220-450.

 

11. Pharmaceutical preparation according to any one of patent claims 1 to 10, characterized in that the patient had a concentration of C-reactive protein over 5 mg/l.

 

12. Pharmaceutical preparation according to any one of patent claims 1 to 11, characterized in that it is prepared for use for a period of 8 weeks or longer.

 

13. A pharmaceutical preparation according to any one of claims 1 to 12, characterized in that laquinimod or its pharmaceutically acceptable salt is in the form of laquinimod sodium.

 

14. A pharmaceutical preparation characterized by essentially consisting of a certain amount of laquinimod or its pharmaceutically acceptable salt, effective in the treatment of a patient suffering from Crohn's disease and a certain amount of 5-aminosalicylic acid, antibiotics, corticosteroids, immunosuppressants, TNF� agents or anti-integrins .

 

15. Use of a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a patient suffering from Crohn's disease.

 

 

Teva Pharmaceutical Industries Ltd.

5 Basel Street P.O. Box 3190

49131 Petach-Tikva, ISRAEL

 

 

Representative:

 

 

 

Treatment of Crohn's disease with laquinimod

 

Abstract

 

 

 

The present invention provides a pharmaceutical preparation for use in the treatment of a patient suffering from Crohn's disease, which contains laquinimod or a pharmaceutically acceptable salt thereof, and which is effective in the treatment of a patient suffering from Crohn's disease. Teva Pharmaceutical Industries Ltd. 5 Basel Street P.O. Box 3190 49131 Petach-Tikva, ISRAEL     Representative:

 

 

 

 

 

Teva Pharmaceutical Industries Ltd.

5 Basel Street P.O. Box 3190

49131 Petach-Tikva, ISRAEL

 

 

Representative:

 

 

 

Claims (15)

1. A pharmaceutical preparation for use in the treatment of a patient suffering from Crohn's disease, characterized in that it contains a pharmaceutically acceptable carrier and a certain amount of laquinimod or its pharmaceutically acceptable salt, and which is effective in the treatment of a patient suffering from Crohn's disease. 2. Pharmaceutical preparation according to patent claim 1, characterized in that it essentially consists of one or more pharmaceutically acceptable carriers and a certain amount of laquinimod or its pharmaceutically acceptable salt. 3. Pharmaceutical preparation according to patent claims 1 or 2, characterized in that the specified amount of laquinimod is effective in alleviating the symptoms of Crohn's disease in the patient, inducing a clinical response, inducing or maintaining clinical remission, inhibiting the progress of the disease or inhibiting the complication of the disease in the said patient. 4. Pharmaceutical preparation according to patent claims 1 or 2, characterized in that the specified amount of laquinimod is effective in reducing the activity index of Crohn's disease in a patient, reducing the concentration of C-reactive protein in a patient, reducing the concentration of fecal calprotectin in a patient or reducing the number of open draining fistulas in a patient of the said patient. 5. Pharmaceutical preparation according to any one of patent claims 1 to 4, characterized in that it is prepared for oral administration. 6. Pharmaceutical preparation according to any one of patent claims 1 to 5, characterized in that it contains a unit dose of 0.5 mg of laquinimod or its pharmaceutically acceptable salt. 7. Pharmaceutical preparation according to any one of patent claims 1 to 6, characterized in that it is prepared for administration once a day. 8. Pharmaceutical preparation according to any one of patent claims 1 to 7, characterized in that it is formulated for the use of laquinimod or its pharmaceutically acceptable salt in a dose of 0.5-2.0 mg per day. 9. Pharmaceutical preparation according to any one of claims 1 to 8, characterized in that the patient suffered from moderate to severe Crohn's disease. 10. A pharmaceutical preparation according to any one of claims 1 to 9, characterized in that the patient had a score on the Crohn's Disease Activity Index of 220-450. 11. Pharmaceutical preparation according to any one of patent claims 1 to 10, characterized in that the patient had a concentration of C-reactive protein over 5 mg/l. 12. Pharmaceutical preparation according to any one of patent claims 1 to 11, characterized in that it is prepared for use for a period of 8 weeks or longer. 13. A pharmaceutical preparation according to any one of claims 1 to 12, characterized in that laquinimod or its pharmaceutically acceptable salt is in the form of laquinimod sodium. 14. A pharmaceutical preparation characterized by essentially consisting of a certain amount of laquinimod or its pharmaceutically acceptable salt, effective in the treatment of a patient suffering from Crohn's disease and a certain amount of 5-aminosalicylic acid, antibiotics, corticosteroids, immunosuppressants, TNF� agents or anti-integrins . 15. Use of a therapeutically effective amount of laquinimod or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a patient suffering from Crohn's disease.